DNA, cis-Platinum and Intercalators: Catalytic Activity of the DNA Double Helix

Abstract

Several drugs have cellular DNA as target. Some act by binding reversibly to DNA, while others bind covalently (Waring 1981). The binding sites are located within the grooves or between the base pairs of the double helix. They vary greatly in size from one to several nucleotide residues and their intrinsic properties are modulated by the DNA molecule itself through short- and long-range interactions. Short-range interactions are dictated by the neighboring nucleotide residues which affect hydration, electrostatic potential, and the accessibility of the binding sites. Long-range interactions result from an event (DNA bending, DNA supercoiling, DNA-protein complexes) on the same DNA molecule but far away from the binding site (Wang and Giaever 1988). The covalent binding of the chemical carcinogen N-acetoxy-N-acetyl-aminofluorene to the C(8) of guanine residues in a plasmid containing a (dC-dG)n insert illustrates the importance of these interactions. In the relaxed plasmid all the guanine residues react with the carcinogen but to a different extent. When the insert is driven into the Z structure by negative supercoiling, the guanine residues within the insert lose their reactivity with the carcinogen, whereas the guanine residues at the B-Z junctions become much more reactive than the more reactive guanine residues in the rest of the plasmid (Marrot et al. 1987).